Methods of treating headaches and photophobia

Abstract

Disclosed herein are methods of treating or preventing headaches (e.g., migraines) and / or photophobia in a subject comprising administering a pharmaceutical composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CORP antagonist.

Description

[0001] Attorney Docket No.: STW-00125

[0002] METHODS OF TREATING HEADACHES AND

[0003] PHOTOPHOBIA

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS

[0005] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 701,649, filed October 1, 2024, which is incorporated by reference herein in its entirety.

[0006] BACKGROUND

[0007] It’s estimated that nearly 40 million Americans suffer from migraines. Approximately 10-20% of all women suffer from migraines so there is a tremendous market share for the application of drugs that prevent or abort acute migraine headaches. As a reflection of this, there have been no fewer than 9 new drugs approved for migraines within the past several years.

[0008] One of the major symptoms of migraines is photophobia. Also, patients with a history of traumatic brain injury may not experience active headaches but have significant photophobia. In other words, patients with a history of traumatic brain injury may experience headaches and / or photophobia. Traumatic brain injury is common, with a 24.6% lifetime prevalence of concussion / mild TBI. Acute post-traumatic headache (PTH) is highly disabling and one of the most common sequelae of concussion, reported in up to 60% of patients within 2 weeks post injury. Amongst those with PTH, over 50% reported persistent headaches at 3 months. Photophobia (visual discomfort in response to normal light level) is one of the most common complaints after concussion.

[0009] Currently, there are no treatments on the market for headaches and photophobia related to traumatic brain injury. There is an expanding catalog of systemic migraine treatments, most of which are oral, sublingual, or nasal. Nasal sprays are often undesirable, uncomfortable and messy. Because nausea is a frequent component of migraine, an alternative to oral route of administration is needed.

[0010] SUMMARY OF THE INVENTION

[0011] In certain aspects, provided herein are methods of treating or preventing a headache (e.g., a migraine or a cluster headache) or photophobia in a subject comprising administering to the exterior surface of an eye of the subject a composition comprising:

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[0013] FH13060928.6 Attorney Docket No.: STW-00125

[0014] 1.2 % (w / v) sumatriptan, or a pharmaceutically acceptable salt thereof, and an ophthalmologically acceptable carrier.

[0015] In certain aspects, provided herein are pharmaceutical compositions formulated for ophthalmic administration, comprising 1.2 % (w / v) sumatriptan, or pharmaceutically acceptable salts thereof, and an ophthalmologically acceptable carrier.

[0016] In certain aspects, provided herein are methods of treating or preventing a migraine or a cluster headache in a subject comprising administering a composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist, or pharmaceutically acceptable salts thereof, and an ophthalmologically acceptable carrier to the exterior surface of an eye of said subject.

[0017] In certain aspects, provided herein are methods of treating or preventing a headache in a subject comprising administering a composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist, or pharmaceutically acceptable salts thereof, and an ophthalmologically acceptable carrier to the exterior surface of an eye of said subject.

[0018] In certain aspects, provided herein are methods of treating or preventing photophobia in a subject comprising administering a composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP agonist, or pharmaceutically acceptable salts thereof, and an ophthalmologically acceptable carrier to the exterior surface of an eye of said subject.

[0019] In certain aspects, provided herein are pharmaceutical compositions formulated for ophthalmic administration, comprising two or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist, or pharmaceutically acceptable salts thereof.

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] A topical eye drop for treating migraines and other neurological conditions (such as post-traumatic headaches) is desirable for a number of reasons. Firstly, it provides an alternate medication route for patients suffering from nausea. Topical administration also bypasses first-pass effect resulting in more rapid onset. Additionally, no current migraine medications specifically address the ocular manifestations of migraines, e.g., red eye(s), ptosis, photophobia. Many migraine patients also suffer from dry eye. Ocular administration may also provide a more targeted or localized approach, e.g., targeting the retrobulbar area and direct trigeminal nerve pathways that mediate migraine pain and its

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[0023] FH13060928.6 Attorney Docket No.: STW-00125 associated symptoms. Use of an eye drop can target the specific organ and provide rapid feedback to neural circuits via the ocular surface which is rich in afferent trigeminal nerve endings. Moisturizing the ocular surface may also be helpful due to the significant overlap between patients experiencing migraines and dry eye. This may also help treat retro-orbital symptoms which are common in migraines and other types of headache. For example, cluster headaches present with red eye (conjunctival injection) and droopy lid (ptosis).

[0024] One of the major symptoms of migraines is photophobia. Also, patients with a history of traumatic brain injury may not experience active headaches but have significant photophobia. In other words, patients with a history of traumatic brain injury may experience headaches and / or photophobia. Currently, there are no treatments on the market for headache and / or photophobia related to traumatic brain injury.

[0025] A list of exemplary migraine medications is shown in Table 1.

[0026] Table 1. List of exemplary migraine medications Oxymetazoline, a selective alpha- 1 adrenergic agonist, was first synthesized in the early 1960s and initially marketed as a nasal decongestant. Its ocular applications emerged in the 1980s, leveraging its vasoconstrictive properties to reduce eye redness and swelling. The U.S. Food and Drug Administration (FDA) approved oxymetazoline for over-the-counter use

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[0028] FH13060928.6 Attorney Docket No.: STW-00125 in eye care products in 1986. Typically, ocular formulations contain oxymetazoline at concentrations of 0.05% to 0.025%, effectively managing conditions like allergic conjunctivitis and dry eye by reducing conjunctival hyperemia. More recently, the FDA approved 0.1% oxymetazoline, for the treatment of acquired blepharoptosis (drooping eyelids), demonstrating its expanded therapeutic utility.

[0029] Timolol, a non-selective beta-adrenergic antagonist, was first introduced in the 1970s as an oral medication for managing hypertension. Its significant breakthrough in ophthalmology came with its approval by the U.S. Food and Drug Administration (FDA) in 1978 for topical use in treating glaucoma. Timolol works by reducing intraocular pressure through decreased aqueous humor production. As one of the first and most widely used betablockers in ocular therapy, timolol remains a cornerstone in glaucoma management, available in various formulations, including Timoptic® and Betimol®, and is notable for its efficacy in lowering intraocular pressure and preserving vision in patients with open-angle glaucoma.

[0030] Triptans, selective 5-HT1B / 1D receptor agonists, have been available since 1991. Six of these drugs are currently available in the US, including sumatriptan (Imitrex), ahnotriptan (Axert), eletriptan (Relpax), ffovatriptan (Frova Vemalis), naratriptan (Amerge), zolmitriptan (Zomig), and rizatriptan (Maxalt). The fastest acting formulations are subcutaneous sumatriptan or a zolmitriptan nasal spray. Sumatriptan is also available in a nasal spray and both zolmitriptan and rizatriptan are available as orally disintegrating tablets. Frovatriptan and naratriptan both have a longer half-life and lower rate of recurrent headaches.

[0031] Sumatriptan may be administered orally, subcutaneously, or via nasal spray. But there is no eye drop formulation on the market. A topical formulation of sumatriptan was reported in animals for cornea pain. Additionally, an off-label human trial to treat cornea pain was reported. It was found to be safe but no more effective than placebo.

[0032] Oral sumatriptan, a selective serotonin receptor agonist, has been studied in a pilot trial for PTH, demonstrating high response rates. In this study, 72% (88 / 122) of headaches resolved within two hours after medication intake. Importantly, the efficacy was consistent across different headache phenotypes — migraine-like (58%), probable migraine-like (83%), and non-migraine-like (40%) — with no significant differences observed (p=0.154). However, the impact on photophobia was not assessed.

[0033] Studies of sumatriptan in PTH also involve veterans. Erickson et al. reported that 70% of PTH patients using triptans achieved reliable headache relief within two hours, compared to 42% using other abortive medications (p=0.01). Effectiveness was seen in both blast- related and non-blast PTH (66% vs. 86%, p=0.20), indicating broad applicability.

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[0035] FH13060928.6 Attorney Docket No.: STW-00125

[0036] There is strong neuroanatomical support for developing an ophthalmic form of sumatriptan to treat post-TBI headache and photophobia, both largely mediated by the thalamus. The thalamus receives input from the trigeminal nerve, which plays a central role in the trigeminovascular system — a network linking the trigeminal nerve to cranial blood vessels and the dura mater. The ocular surface, particularly the cornea, is densely innervated by trigeminal nerve endings via the ophthalmic branch, which provides a direct pathway for sumatriptan to exert its beneficial effect.

[0037] Additional support for topical application of sumatriptan is based at the molecular level. Sumatriptan acts primarily as an agonist at the 5-HTiB and 5-HTiD receptors, modulating serotonin pathways implicated in headache pathophysiology. Cornea epithelial cells also express serotonin receptor subtypes, including 5-HT7. Calcitonin gene-related peptide (CGRP), a neuropeptide released in trigeminovascular activation, plays a key role in migraine, photophobia, and TBI pathophysiology. Sumatriptan inhibits CGRP release which can help reduce these elements.

[0038] Inflammation is also thought to play a significant role in TBI. Several mechanisms are implicated. For example, activated microglia and astrocytes secrete pro-inflammatory cytokines that disrupt neuronal function and contribute to sensory hypersensitivity. Additionally, trigeminal nerve sensitization after TBI leads to increased excitability and enhanced light sensitivity. The robust inflammatory response includes activation of microglia and astrocytes, which release pro-inflammatory cytokines such as IL- 1 P, TNF-a, and IL-6. Sumatriptan, even at low doses, reduces inflammatory mediators including IL-ip, TNF-a, NF-KB, caspases, and nitric oxide synthase. These antiinflammatory effects may mitigate neuronal hyperexcitability and sensory hypersensitivity underlying photophobia.

[0039] Approved by the FDA since 1992, sumatriptan is available in oral, subcutaneous, nasal, and injectable formulations. However, no ophthalmic formulation is approved. In embodiments of the present disclosure, ophthalmic sumatriptan offers several advantages: -direct targeting of trigeminal pathways between the eye and brain -reduce first-pass effect -lower doses due to localized delivery -better tolerability compared to nasal sprays -rapid onset

[0040] -reduced systemic side effects (e.g., chest tightness, throat constriction) -circumvention of nausea common in TBI patients.

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[0042] FH13060928.6 Attorney Docket No.: STW-00125

[0043] In certain aspects, the present invention provides topical methods of treatment comprising conjointly administering one or more agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist. In certain embodiments, conjoint administration of the agents results in a synergistic effect. Combination therapy may also be advantageous because different patients respond to different medications, particularly when medications have different mechanisms of action. For example, sumatriptan affects trigeminal pain processing, while beta blockers do not.

[0044] Topical timolol, a beta blocker eye drop, which is available as a generic pharmaceutical agent and used for many decades on-label to treat glaucoma, has been used off-label to abort acute migraines. It is not FDA approved for this indication (but has been studied in the literature, with varying results). Treatment with sumatriptan constricts blood vessels and can be associated with systemic serotonin syndrome (e.g., tachycardia, labile blood pressure) or myocardial ischemia. The interaction of beta blockers with these side effects is not clear. There are conflicting reports on use of beta blockers to treat serotonin syndrome. For example, while esmolol is mentioned as a treatment, propranolol is contraindicated. Timolol, which is structurally similar to propranolol, would not be expected to have a beneficial effect with sumatriptan. Indeed, sumatriptan has been reported to cause glaucoma, whereas timolol can be used to treat glaucoma. However, in a topical migraine treatment, the inventors have found that they may act synergistically e.g., rapid onset of action and reduction in symptoms. Patients may experience recurrent headaches after sumatriptan treatment. Without wishing to be bound by a theory, the longer half-life of timolol may reduce the headache recurrence.

[0045] Additional therapeutic agents may provide benefits when administered in combination with sumatriptan, such as alpha agonists and CGRP antagonists. Alpha agonists (e.g., apraclonidine or brimonidine) are sympathomimetic and largely analogous to adrenaline or norepinephrine (i.e., mimicking the “fight or flight” response). Pupil dilation would be expected upon topical administration of an alpha agonist. To have pupil constriction (e.g., brimonidine) or no pupil dilation (e.g., oxymetazoline) would be unexpected. Without wishing to be bound by a theory, the cerebral vasoconstriction activity associated with alpha agonists (e.g., oxymetazoline) may be synergistic with sumatriptan due to different mechanisms of action. For example, sumatriptan is rapidly absorbed in the thalamus whereas oxymetazoline (via the olfactory route) does not pass the thalamus before reaching cortical regions. It would not be expected that a topical formulation including oxymetazoline would help treat migraine because: (1) it reduces blood flow to nasal mucosa which should

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[0047] FH13060928.6 Attorney Docket No.: STW-00125 theoretically reduce uptake of any other drug (2) oxymetazoline has headache listed as an adverse effect.

[0048] To date, CGRP antagonists have not been reported as eye drops.

[0049] Further, the addition of therapeutic agents such as timolol, oxymetazoline, and zavegepant to a solution of sumatriptan having a relatively low pH (range 4.2-5.5) may increase the pH of the formulation to closer to neutral and therefore reduce stinging upon ocular administration.

[0050] In certain preferred aspects, provided herein are methods of treating or preventing a headache (e.g., a migraine or a cluster headache) or photophobia in a subject comprising administering to the exterior surface of an eye of the subject a composition comprising: 1.2 % (w / v) sumatriptan, or a pharmaceutically acceptable salt thereof, and an ophthahnologically acceptable carrier. In certain preferred embodiments, the headache or the photophobia result from traumatic brain injury.

[0051] In certain preferred aspects, provided herein are pharmaceutical compositions formulated for ophthalmic administration, comprising 1.2 % (w / v) sumatriptan, or pharmaceutically acceptable salts thereof, and an ophthahnologically acceptable carrier.

[0052] In certain aspects, provided herein is a method of treating or preventing a migraine or a cluster headache in a subject comprising administering a composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist, or pharmaceutically acceptable salts thereof, and an ophthahnologically acceptable carrier to the exterior surface of an eye of said subject.

[0053] In certain embodiments, the method treats or prevents the migraine. In certain embodiments, the method treats or prevents the cluster headache.

[0054] In certain aspects, provided herein are methods of treating or preventing a headache in a subject comprising administering a composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist, or pharmaceutically acceptable salts thereof, and an ophthalmologically acceptable carrier to the exterior surface of an eye of said subject.

[0055] In certain embodiments, the headache is a migraine. In certain embodiments, the headache is a cluster headache. In certain embodiments, the headache is selected from the

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[0057] FH13060928.6 Attorney Docket No.: STW-00125 group consisting of cluster headache, tension-type headache, and medication overuse headache.

[0058] In certain embodiments, the headache is the result of a neurological condition. In certain preferred embodiments, the neurological condition is traumatic brain injury.

[0059] In certain aspects, provided herein is a method of treating or preventing photophobia in a subject comprising administering a composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP agonist, or pharmaceutically acceptable salts thereof, and an ophthalmologically acceptable carrier to the exterior surface of an eye of said subject.

[0060] In certain embodiments, the photophobia is the result of a neurological condition. In certain preferred embodiments, the neurological condition is traumatic brain injury. In certain embodiments, the neurological condition is due to neurosurgery. In certain embodiments, the neurological condition is a concussion.

[0061] In certain embodiments, the composition comprises a triptan. In certain embodiments, the composition comprises a CGRP antagonist. In certain embodiments, the composition comprises a beta blocker. In certain embodiments, the composition comprises an alpha agonist.

[0062] In certain embodiments, the method comprises administering two or more therapeutic agents conjointly. In certain embodiments, the two or more of the therapeutic agents are administered concomitantly. In certain embodiments, the two or more of the therapeutic agents are administered sequentially.

[0063] In certain embodiments, the composition comprises a triptan and a beta blocker. In certain embodiments, the composition comprises a triptan and a CGRP antagonist. In certain embodiments, the composition comprises a beta blocker and a CGRP antagonist. In certain embodiments, the composition comprises a beta blocker and an alpha agonist. In certain embodiments, the composition comprises a triptan, a beta blocker, and an alpha agonist.

[0064] In certain embodiments, the composition comprises a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist.

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[0066] FH13060928.6 Attorney Docket No.: STW-00125

[0067] In certain embodiments, the triptan is selected from sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, zolmitriptan, and rizatriptan. In certain preferred embodiments, the triptan is sumatriptan.

[0068] In certain embodiments, the beta blocker is selected from timolol, esmolol, and propranolol. In certain embodiments, the beta blocker is timolol.

[0069] In certain embodiments, the alpha agonist is selected from apraclonidine, oxymetazoline, oxymetazoline hydrochloride, and brimonidine. In certain embodiments, the alpha agonist is oxymetazoline. In certain embodiments, the alpha agonist is oxymetazoline hydrochloride.

[0070] In certain embodiments, the CGRP antagonist is selected from ubrogepant, Rimegepant, zavegepant. In certain embodiments, the CGRP antagonist is zavegepant.

[0071] In certain embodiments, the composition comprises a triptan and timolol. In certain embodiments, the composition comprises sumatriptan and a beta blocker. In certain embodiments, the composition comprises sumatriptan and timolol. In certain embodiments, the composition comprises sumatriptan and a CGRP antagonist. In certain embodiments, the composition comprises a triptan and zavegepant. In certain embodiments, the composition comprises sumatriptan and Zavegepant. In certain embodiments, the composition comprises a beta blocker and zavegepant. In certain embodiments, the composition comprises timolol and a CGRP antagonist. In certain embodiments, the composition comprises timolol and zavegepant. In certain embodiments, the composition comprises a beta blocker and oxymetazoline. In certain embodiments, the composition comprises a beta blocker and oxymetazoline hydrochloride. In certain embodiments, the composition comprises timolol and an alpha agonist. In certain embodiments, the composition comprises timolol and oxymetazoline. In certain embodiments, the composition comprises timolol and oxymetazoline hydrochloride.

[0072] In certain embodiments, the composition comprises sumatriptan, timolol, and an alpha agonist. In certain embodiments, the composition comprises sumatriptan, timolol, and oxymetazoline. In certain embodiments, the composition comprises sumatriptan, timolol, and oxymetazoline hydrochloride. In certain embodiments, the composition comprises a triptan, timolol, and oxymetazoline. In certain embodiments, the composition comprises a triptan, timolol, and oxymetazoline hydrochloride. In certain embodiments, the composition

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[0074] FH13060928.6 Attorney Docket No.: STW-00125 comprises sumatriptan, a beta blocker, and oxymetazoline. In certain embodiments, the composition comprises sumatriptan, a beta blocker, and oxymetazoline hydrochloride.

[0075] In certain embodiments, the composition comprises sumatriptan, timolol, oxymetazoline, and a CGRP antagonist. In certain embodiments, the composition comprises sumatriptan, timolol, oxymetazoline hydrochloride, and a CGRP antagonist. In certain embodiments, the composition comprises sumatriptan, timolol, oxymetazoline, and zavegepant. In certain embodiments, the composition comprises sumatriptan, timolol, oxymetazoline hydrochloride, and zavegepant. hi certain embodiments, the composition comprises a triptan, timolol, oxymetazoline, and zavegepant. In certain embodiments, the composition comprises a triptan, timolol, oxymetazoline hydrochloride, and zavegepant. In certain embodiments, the composition comprises a triptan, a beta blocker, oxymetazoline, and zavegepant. In certain embodiments, the composition comprises a triptan, a beta blocker, oxymetazoline hydrochloride, and zavegepant. In certain embodiments, the composition comprises a triptan, timolol, an alpha agonist, and zavegepant.

[0076] In certain preferred embodiments, the composition comprises between about 0.1 to between about 2.4 weight percent sumatriptan. In particularly preferred embodiments, the composition comprises about 1.2 weight percent sumatriptan.

[0077] In certain embodiments, the composition comprises between about 0.25 to between about 1 weight percent timolol. In certain embodiments, the composition comprises about 0.5 weight percent timolol.

[0078] In certain embodiments, the composition comprises between about 0.05 to between about 0.2 weight percent oxymetazoline hydrochloride. In certain embodiments, the composition comprises about 0.1 weight percent oxymetazoline hydrochloride.

[0079] In certain embodiments, the composition comprises between about 0.05 to between about 0.1 weight percent zavegepant. In certain embodiments, the composition comprises about 0.1 weight percent zavegepant.

[0080] In certain embodiments, the composition further comprises ivermectin, etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, oxytocin, levodopa / carbidopa, caffeine, topiramate, amitryptiline, valproic acid, ergotamines, gabapentin, lotilaner, ebselen, or blue dye, or any combination thereof. In certain embodiments, the composition does not

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[0082] FH13060928.6 Attorney Docket No.: STW-00125 include a preservative. In certain embodiments, the pH of the composition is from about 5 to about 7. In certain embodiments, the pH of the composition is about 7. In certain embodiments, the composition comprises a lubricant, such as artificial tears, white petrolatum, or mineral oil.

[0083] In certain embodiments, the method further comprises administering the composition to both eyes.

[0084] In certain embodiments, the subject has nausea. In certain embodiments, the subject has dry eye. In certain embodiments, the method reduces pupil size. In certain embodiments, the method reduces red eye. In certain embodiments, the method reduces ptosis, hi certain embodiments, the method reduces headache symptoms. In certain embodiments, the method does not cause chest tightness and / or throat constriction. In certain embodiments, the method reduces photophobia.

[0085] In certain embodiments, the composition is preservative-free.

[0086] In certain aspects, provided herein are a pharmaceutical composition formulated for ophthalmic administration, comprising two or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist, or pharmaceutically acceptable salts thereof.

[0087] In certain embodiments, the composition comprises a triptan and a beta blocker. In certain embodiments, the composition comprises a triptan and a CGRP antagonist. In certain embodiments, the composition comprises a beta blocker and a CGRP antagonist. In certain embodiments, the composition comprises a beta blocker and an alpha agonist.

[0088] In certain embodiments, the composition comprises a triptan, a beta blocker, and an alpha agonist.

[0089] In certain embodiments, the composition comprises a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist.

[0090] In certain embodiments, the triptan is selected from sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, zolmitriptan, and rizatriptan. In certain embodiments, the triptan is sumatriptan.

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[0093] In certain embodiments, the beta blocker is selected from timolol, esmolol, and propranolol. In certain embodiments, the beta blocker is timolol.

[0094] In certain embodiments, the alpha agonist is selected from apraclonidine, oxymetazoline, oxymetazoline hydrochloride, and brimonidine. In certain embodiments, the alpha agonist is oxymetazoline. In certain embodiments, the alpha agonist is oxymetazoline hydrochloride.

[0095] In certain embodiments, the CGRP antagonist is selected from ubrogepant, Rimegepant, Zavegepant. In certain embodiments, the CGRP antagonist is zavegepant.

[0096] In certain embodiments, the composition comprises a triptan and timolol. In certain embodiments, the composition comprises sumatriptan and a beta blocker. In certain embodiments, the composition comprises sumatriptan and timolol. In certain embodiments, the composition comprises sumatriptan and a CGRP antagonist. In certain embodiments, the composition comprises a triptan and zavegepant. In certain embodiments, the composition comprises sumatriptan and zavegepant. In certain embodiments, the composition comprises a beta blocker and zavegepant. In certain embodiments, the composition comprises timolol and a CGRP antagonist. In certain embodiments, the composition comprises timolol and zavegepant. In certain embodiments, the composition comprises a beta blocker and oxymetazoline. In certain embodiments, the composition comprises a beta blocker and oxymetazoline hydrochloride. In certain embodiments, the composition comprises timolol and an alpha agonist. In certain embodiments, the composition comprises timolol and oxymetazoline. In certain embodiments, the composition comprises timolol and oxymetazoline hydrochloride.

[0097] In certain embodiments, the composition comprises sumatriptan, timolol, and an alpha agonist. In certain embodiments, the composition comprises sumatriptan, timolol, and oxymetazoline. In certain embodiments, the composition comprises sumatriptan, timolol, and oxymetazoline hydrochloride. In certain embodiments, the composition comprises a triptan, timolol, and oxymetazoline. In certain embodiments, the composition comprises a triptan, timolol, and oxymetazoline hydrochloride. In certain embodiments, the composition comprises sumatriptan, a beta blocker, and oxymetazoline. In certain embodiments, the composition comprises sumatriptan, a beta blocker, and oxymetazoline hydrochloride.

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[0100] In certain embodiments, the composition comprises sumatriptan, timolol, oxymetazoline, and a CGRP antagonist. In certain embodiments, the composition comprises sumatriptan, timolol, oxymetazoline hydrochloride, and a CGRP antagonist. In certain embodiments, the composition comprises sumatriptan, timolol, oxymetazoline, and zavegepant. In certain embodiments, the composition comprises sumatriptan, timolol, oxymetazoline hydrochloride, and zavegepant. In certain embodiments, the composition comprises a triptan, timolol, oxymetazoline, and zavegepant. In certain embodiments, the composition comprises a triptan, timolol, oxymetazoline hydrochloride, and zavegepant.

[0101] In certain embodiments, the composition comprises a triptan, a beta blocker, oxymetazoline, and zavegepant. In certain embodiments, the composition comprises a triptan, a beta blocker, oxymetazoline hydrochloride, and zavegepant. In certain embodiments, the composition comprises a triptan, timolol, an alpha agonist, and zavegepant.

[0102] In certain embodiments, the composition comprises between about 0.1 to about 2.4 weight percent sumatriptan. In certain embodiments, the composition comprises about 1.2 weight percent sumatriptan.

[0103] In certain embodiments, the composition comprises between about 0.25 to about 1 weight percent timolol. In certain embodiments, the composition comprises about 0.5 weight percent timolol.

[0104] In certain embodiments, the composition comprises between about 0.05 to about 0.2 weight percent oxymetazoline. In certain embodiments, the composition comprises about 0.1 weight percent oxymetazoline.

[0105] In certain embodiments, the composition comprises between about 0.05 to about 0.2 weight percent oxymetazoline hydrochloride. In certain embodiments, the composition comprises about 0.1 weight percent oxymetazoline hydrochloride.

[0106] In certain embodiments, the composition comprises between about 0.05 to between about 0.1 weight percent zavegepant. In certain embodiments, the composition comprises about 0.1 weight percent zavegepant.

[0107] In certain embodiments, the composition further comprises ivermectin, etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, oxytocin, levodopa / carbidopa, caffeine, topiramate, amitryptiline, valproic acid, ergotamines, gabapentin, lotilaner, ebselen,

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[0109] FH13060928.6 Attorney Docket No.: STW-00125 blue dye, or any combination thereof. In certain embodiments, the composition does not include a preservative. In certain embodiments, the pH of the composition is between around 5 to around 7. In certain embodiments, the pH of the composition is around 7. In certain embodiments, the composition comprises a lubricant, such as artificial tears, white petrolatum, or mineral oil.

[0110] In certain embodiments, the composition is preservative-free.

[0111] Definitions

[0112] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.

[0113] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0114] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0115] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0116] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants,

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[0118] FH13060928.6 Attorney Docket No.: STW-00125 fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known.

[0119] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0120] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0121] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0122] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered ocularly, such as topically on the eye. A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0123] 15

[0124] FH13060928.6 Attorney Docket No.: STW-00125

[0125] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0126] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0127] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0128] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.

[0129] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0130] 16

[0131] FH13060928.6 Attorney Docket No.: STW-00125

[0132] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

[0133] The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formula I. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0134] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

[0135] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

[0136] The term “eye” refers inclusively to any portion of the surface of an eye or the surrounding ocular anatomy. This includes, without limitation, any or all of the following structures: the cornea; the conjunctiva, including the palpebral and bulbar conjunctiva; the tear sac; the eyelid, including the internal and external eyelid surface; eyelashes,; ocular area; ocular tissues; eye area tissue; eyelid margin; front of the eye; under the upper eyelid; on the 17

[0137] FH13060928.6 Attorney Docket No.: STW-00125 lower eyelid the lachrymal glad; and / or the cul-de-sac. Preferred areas for ocular administration include the eyelid, eyelid margin, palpebral conjunctiva, and / or bulbar conjunctiva.

[0138] As used herein, an “ophthalmologically acceptable carrier” is any pharmaceutically acceptable carrier that is suitable for topical administration to the eye.

[0139] EXAMPLES

[0140] Example 1: Effect of Therapeutic Agents on Migraine Headache and Ocular Symptoms

[0141] Patients were treated with 1.2 wt. %, sumatriptan, 0.5 wt. % timolol, 0.1 wt. % oxymetazoline, or combinations thereof. Drops were applied in both eyes. Treatment was initiated as quickly as possible within the onset of migraine symptoms (usually within 15-30 min); 1 drop was applied once in each eye. Rescue doses of medications were not included in the data. Results are shown in Tables 2 and 3.

[0142] Table 2. Effect of individual and combination therapy on headache and ocular symptoms

[0143] Average Headache improvement (%) and Average Eye Improvement (%) was calculated as follows: Maximum intensity - Minimum intensity / maximum intensity x 100

[0144] Table 3. Individual and Combination Therapies on headache and ocular symptoms.

[0145] 18

[0146] FH13060928.6 Attorney Docket No.: STW-00125

[0147] Headache total relief (%) and Eye total relief (%): % of Encounters with complete relief

[0148] Sumatriptan constricts blood vessels whereas beta blockers relax blood vessels. For example, sumatriptan can cause myocardial ischemia. Beta blockers are used to treat myocardial ischemia. Administration of beta blockers would therefore be expected to counter the effects of sumatriptan. Surprisingly, in a topical migraine treatment of a composition comprising sumatriptan, timolol, and oxymetazoline, the therapeutic agents act synergistically in terms of onset of action as well as reduction in symptoms (Table 2). Specifically, patients treated with timolol, sumatriptan, and oxymetazoline experienced a significant reduction in time to achieve maximum effect for headache symptoms (25 minutes as compared to >50 for timolol or sumatriptan alone). It should be noted that patients treated with oxymetazoline alone did not experience any alleviation in headache symptoms (in some previous clinical trials headache has been reported as an adverse effect of topical oxymetazoline administration). A similar effect was observed for ocular symptoms (22 minutes as compared to >55 minutes for timolol or sumatriptan alone).

[0149] Table 3 shows that a larger percentage of patients treated with a combination of timolol, sumatriptan, and oxymetazoline experience more total headache relief (75% as compared to 43% for patients treated with sumatriptan alone, and 0% for patients treated with timolol, oxymetazoline alone and a combination of sumatriptan and oxymetazoline). Additionally, patents treated with a combination of timolol, sumatriptan, and oxymetazoline experienced more rapid total headache relief (21 minutes as compared to 64 minutes for

[0150] 19

[0151] FH13060928.6 Attorney Docket No.: STW-00125 sumatriptan alone). While treatment with Oxymetazoline alone results in rapid activity for ocular symptoms, no effect on headache symptoms is observed.

[0152] The results show that a combination of sumatriptan, timolol, and oxymetazoline is both more effective and acts more rapidly than individual components for the treatment of both headache and ocular symptoms.

[0153] Example 2: Phase I protocol for a Double-Masked, Placebo-Controlled, Crossover Pilot Study to Evaluate the Safety and Tolerability of Sumatriptan 1.2% Eve Drops in Adults with Post-Traumatic Headache and Photophobia

[0154] A small, double-masked, placebo-controlled crossover trial in 10-15 patients with TBI-related headaches and photophobia is proposed in Example 2. Primary endpoints will assess quantitative subjective headache reduction at 1 hour and 2 hours. Secondary endpoints will include: quantitative subjective photophobia reduction, time to meaningful relief, safety and tolerability. This study aims to establish preliminary safety and efficacy data for topical sumatriptan in this population.

[0155] This study uses topical, preservative-free sumatriptan eye drops (1.2%) that have been compounded from the injectable form. Injectable sumatriptan is easily procured. It has good pH flexibility (stable up to pH 9 and down to pH 2), robust stability (temperature up to 50 °C), half-life of 2.5 hours, and is readily soluble in water and saline. The pH of sumatriptan is approximately 4.2-5.3. The pH may be adjusted to 7.0 to 7.5 with sodium hydroxide 1% in order to make the eye drop comfortable and compatible with the ocular surface. The osmolality is 291 mOsmol.

[0156] The sumatriptan will be prepared under aseptic conditions and delivered on ice. The 3 ml-steri-droptainers will each have 1 ml of sumatriptan 1.2%. The product should be stored for a maximum 10 days (refrigerated) or 30 days (frozen). Vials can be used immediately after removal from the freezer or refrigerator. Vials should be returned to cold temperature as soon as possible. Each vial, once opened, should be discarded after 3 days. Instructions for storage and usage will be given to each patient.

[0157] The saline (control) vials will similarly contain 1 ml of 0.9% normal saline. Of note, both the sumatriptan and saline drops have identical clear appearance making them indistinguishable to the naked eye. Packaging will be identical in order to mask the contents. Furthermore, with pH of 7 in both the sumatriptan and saline, no difference is expected in

[0158] 20

[0159] FH13060928.6 Attorney Docket No.: STW-00125 sensation (e.g., buming / stinging) between the study drug and placebo. Preservative-free vials may be used.

[0160] Any adverse effects will be carefully observed (see Example 2)). Of note, sumatriptan has been studied on rabbit corneas, human corneas and even with direct injection into rabbit pars plana. Regarding systemic toxicology, it is believed that the general systemic safety profile of sumatriptan has been well established over the last 30 years since its initial approval for treatment of acute migraine. Furthermore, it is estimated that the potential systemic exposure is negligible based on the topical dosing involved.

[0161] Placing one drop of sumatriptan in each eye is akin to “ophthalmic microdosing”.

[0162] Proposed dosage calculations are as follows. Each 0.5 mL of sumatriptan injection contains 8.4 mg of sumatriptan succinate, equivalent to 6 mg of sumatriptan. An average eye drop has a volume of 30-50 microliters (|1L), and the maximum capacity of the tear sac is 30 pL. If 6 mg of sumatriptan are contained in 0.5 mL (500 pL), a 30-pL drop would deliver 0.36 mg of sumatriptan (6 mg / 500 jiL x 30 pL / drop). Assuming 80% systemic absorption from an eye drop, approximately 0.29 mg would be absorbed systemically. For comparison, standard oral doses of sumatriptan are 25 mg, 50 mg, or 100 mg; therefore, the amount (mg) administered in a single eye drop corresponds to approximately 1.4% (relative to 25 mg) to 0.36% (relative to 100 mg) of an oral dose.

[0163] Drug substance:

[0164] Injectable sumatriptan 1.2% reformulated as an eye drop.

[0165] Indication

[0166] Abortive treatment of post-traumatic acute headache and photophobia.

[0167] Inclusion Criteria

[0168] -Symptoms: Post traumatic headache and photophobia. Patients should have at least 1 episode weekly with severity grade 4 or more (on 1-10 visual analog scale)

[0169] -Age range: 18-55 years old

[0170] -Gender: Male and Female

[0171] Intervention

[0172] Sumatriptan 1.2% eye drops (the injectable formulation prepared at a neutral PH by a compounding pharmacy as a sterile, preservative free eye drop). Importantly, the neutral pH

[0173] 21

[0174] FH13060928.6 Attorney Docket No.: STW-00125 of the sumatriptan will preclude buming / stinging which would enable a patient to distinguish it from the placebo.

[0175] Method

[0176] Double masked. Placebo-controlled. Crossover. Patients will be given identical vials, half of which contain medication, half placebo. Each vial will have a numerical code to discern whether it is drug or placebo. To mitigate the result of placebo response, study participants will be masked to the crossover sequential design.

[0177] -Dosing: 1 drop to each eye as close to the onset of headache / photophobia as possible.

[0178] -Maximum usage: one drop to each eye, repeated after two hours if needed (total of 4 drops).

[0179] -Duration of study: 2 weeks on active drug; 2 weeks placebo per patient.

[0180] Safety

[0181] This Phase 1 study emphasizes safety and tolerability of sumatriptan 1.2% ophthalmic solution. Full safety protocol and informed consent is attached separately. These are some fundamental elements:

[0182] -Informed consent will be obtained from each patient.

[0183] -Monitoring: Blood pressure, heart rate and oxygen saturation will be measured before enrollment, midway, and at primary study completion. A safety follow up visit (either in person or by phone) will be conducted 30 days after the study completion. Eye exams will be performed to verify safety and tolerability before enrollment; midway (2 weeks); and at study completion (end of week 4).

[0184] -Specific data points will include: visual acuity, intraocular pressure, pupil measurements, gonioscopy, slit lamp exam, cornea staining. Posterior exam will be done with Optos or CenterVue fundus camera (dilated exam will be deferred unless absolutely necessary to mitigate photophobia in already-sensitive subjects and eliminate the confounding variable of mydriatic drops).

[0185] -All AEs will be collected from time of first dose through 30-day post-study followup

[0186] -AEs will be graded using CTCAE v5.0 for systemic events and NEI Ocular Adverse Event Grading Scale for ocular events.

[0187] 22

[0188] FH13060928.6 Attorney Docket No.: STW-00125

[0189] -Standard operating protocol (SOP) will be followed for serious adverse events (SAE) as outlined in the full study protocol.

[0190] -Adverse Event (AE) Grading and Documentation Log Sheet will be meticulously maintained.

[0191] -All SAEs will be reviewed promptly by DSMB for causality, safety signal detection, and study continuation recommendations.

[0192] -Life-threatening / fatal SAEs: reported to IRB and FDA within 7 calendar days. Other SAE within 15 calendar days.

[0193] -Toxicity-Based Stopping Rules are outlined for both individual participants as well as study-wide.

[0194] -Study medication (sumatriptan and placebo) will be stored at appropriate temperature per compounding pharmacy guidelines

[0195] -Patients will receive printed instructions on use, storage, and when to seek care -24-hour contact line for study-related concerns will be provided

[0196] -Rescue medications (e.g., NSAIDs, acetaminophen) permitted and tracked

[0197] -Pregnant participants will be excluded and pregnancy testing conducted prior to enrollment

[0198] -Study will be conducted under Good Clinical Practice (GCP)

[0199] -IRB review and approval required

[0200] -Participant confidentiality and data protection maintained for all patients.

[0201] Data Input

[0202] Paper diaries will be used. Patients will enter their level of headache and photophobia (on a numeric pain reporting scale of 0-10; 10 being the worst). Time points: baseline, 30 minutes, 1 hour, 2 hour, 6 hours after administration. Data will be secured and password- protected on computer.

[0203] Primary endpoints

[0204] % reported reduction in headache / retrobulbar pain. % reported reduction of photophobia; (Mean and median reduction per episode / per day as well as per week will be observed)

[0205] Secondary endpoints:

[0206] Time to meaningful relief of headache / photophobia.

[0207] 23

[0208] FH13060928.6 Attorney Docket No.: STW-00125

[0209] Recurrence / Rescue:

[0210] Recurrence rates will be recorded. If rescue medication is needed, additional 1 drop in each eye can be applied 2 hours after initial installation. Repeat dosing is not considered rescue but the use of a second dose will be tracked and reported as an outcome measure. Rescue medication includes all OTC meds. For example, NSAIDs and acetaminophen can be rescue medications.

[0211] Statistical Analysis

[0212] Random 1:1 adjudication by a blinded party who distributes the vial at enrollment. Descriptive statistics will be used to determine primary and secondary endpoints. No formal hypothesis testing will be performed. Detailed statistical methods will be available in the statistical analysis plan which will be completed prior to study completion.

[0213] INCORPORATION BY REFERENCE

[0214] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0215] EQUIVALENTS

[0216] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0217] 24

[0218] FH13060928.6

Claims

Attorney Docket No.: STW-00125CLAIMSWe claim:

1. A method of treating or preventing a headache (e.g., a migraine or a cluster headache) or photophobia in a subject comprising administering to the exterior surface of an eye of the subject a composition comprising:1.2 % (w / v) sumatriptan, or a pharmaceutically acceptable salt thereof, and an ophthalmologically acceptable carrier.

2. The method of claim 1 , wherein the headache or the photophobia result from traumatic brain injury.

3. A pharmaceutical composition formulated for ophthalmic administration, comprising 1.2 % (w / v) sumatriptan, or a pharmaceutically acceptable salt thereof, and an ophthalmologically acceptable carrier.

4. A method of treating or preventing a headache in a subject comprising administering a composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist, or pharmaceutically acceptable salts thereof, and an ophthalmologically acceptable carrier to the exterior surface of an eye of said subject.

5. The method of claim 4, wherein the headache is a migraine.

6. The method of claim 4, wherein the headache is a cluster headache.

7. The method of claim 4, wherein the headache is selected from the group consisting of cluster headache, tension-type headache, and medication overuse headache.

8. The method of any one of claims 4-7, wherein the headache is the result of a neurological condition.

9. The method of claim 8, wherein the neurological condition is traumatic brain injury.

10. A method of treating or preventing photophobia in a subject comprising administering a composition comprising one or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP agonist, or pharmaceutically acceptable salts thereof, and an ophthalmologically acceptable carrier to the exterior surface of an eye of said subject.25FH13060928.6Attorney Docket No.: STW-0012511. The method of claim 10, wherein the photophobia is the result of a neurological condition.

12. The method of claim 11, wherein the neurological condition is traumatic brain injury.

13. The method of claim 11, wherein the neurological condition is due to neurosurgery.

14. The method of claim 11, wherein the neurological condition is a concussion.

15. The method of any one of claims 4-14, wherein the composition comprises a triptan.

16. The method of any one of claims 4-15, wherein the composition comprises a CGRP antagonist.

17. The method of any one of claims 4-16, wherein the composition comprises a beta blocker.

18. The method of any one of claims 4-17, wherein the composition comprises an alpha agonist.

19. The method of any one of claims 4-18, wherein the method comprises administering two or more therapeutic agents conjointly.

20. The method of claim 19, wherein the two or more of the therapeutic agents are administered concomitantly.

21. The method of claim 19, wherein the two or more of the therapeutic agents are administered sequentially.

22. The method of any one of claims 4-21, wherein the composition comprises a triptan and a beta blocker.

23. The method of any one of claims 4-21, wherein the composition comprises a triptan and a CGRP antagonist.

24. The method of any one of claims 4-21, wherein the composition comprises a beta blocker and a CGRP antagonist.26FH13060928.6Attorney Docket No.: STW-0012525. The method of any one of claims 4-21, wherein the composition comprises a beta blocker and an alpha agonist.

26. The method of any one of claims 4-22, wherein the composition comprises a triptan, a beta blocker, and an alpha agonist.

27. The method of any one of claims 4-26, wherein the composition comprises a triptan, a beta blocker, and alpha agonist, and a CGRP antagonist.

28. The method of any one of claims 4-27, wherein the triptan is selected from sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, zolmitriptan, and rizatriptan.

29. The method of any one of claims 4-28, wherein the triptan is sumatriptan.

30. The method of any one of claims 4-29, wherein the beta blocker is selected from timolol, esmolol, and propranolol.

31. The method of any one of claims 4-30, wherein the beta blocker is timolol.

32. The method of any one of claims 4-31, wherein the alpha agonist is selected from apraclonidine, oxymetazoline, oxymetazoline hydrochloride, and brimonidine.

33. The method of any one of claims 4-32, wherein the alpha agonist is oxymetazoline.

34. The method of any one of claims 4-32, wherein the alpha agonist is oxymetazoline hydrochloride.

35. The method of any one of claims 4-34, wherein the CGRP antagonist is selected from ubrogepant, Rimegepant, zavegepant.

36. The method of any one of claims 4-35, wherein the CGRP antagonist is zavegepant.

37. The method of claim 30, wherein the composition comprises a triptan and timolol.

38. The method of claim 28, wherein the composition comprises sumatriptan and a beta blocker.

39. The method of any one of claims 30-38, wherein the composition comprises sumatriptan and timolol.27FH13060928.6Attorney Docket No.: STW-0012540. The method of claim 28, wherein the composition comprises sumatriptan and a CGRP antagonist.

41. The method of claim 35, wherein the composition comprises a triptan and zavegepant.

42. The method of any one of claims 35-41, wherein the composition comprises sumatriptan and zavegepant.

43. The method of claim 35, wherein the composition comprises a beta blocker and zavegepant.

44. The method of claim 30, wherein the composition comprises timolol and a CGRP antagonist.

45. The method of claim 35, wherein the composition comprises timolol and zavegepant.

46. The method of claim 32, wherein the composition comprises a beta blocker and oxymetazoline.

47. The method of claim 32, wherein the composition comprises a beta blocker and oxymetazoline hydrochloride.

48. The method of claim 30, wherein the composition comprises timolol and an alpha agonist.

49. The method of claim 31, wherein the composition comprises timolol and oxymetazoline.

50. The method of claim 32, wherein the composition comprises timolol and oxymetazoline hydrochloride.

51. The method of claim 30, wherein the composition comprises sumatriptan, timolol, and an alpha agonist.

52. The method of claim 32, wherein the composition comprises sumatriptan, timolol, and oxymetazoline.

53. The method of claim 32, wherein the composition comprises sumatriptan, timolol, and oxymetazoline hydrochloride.28FH13060928.6Attorney Docket No.: STW-0012554. The method of claim 32, wherein the composition comprises a triptan, timolol, and oxymetazoline.

55. The method of claim 32, wherein the composition comprises a triptan, timolol, and oxymetazoline hydrochloride.

56. The method of claim 32, wherein the composition comprises sumatriptan, a beta blocker, and oxymetazoline.

57. The method of claim 32, wherein the composition comprises sumatriptan, a beta blocker, and oxymetazoline hydrochloride.

58. The method of claim 32, wherein the composition comprises sumatriptan, timolol, oxymetazoline, and a CGRP antagonist.

59. The method of claim 32, wherein the composition comprises sumatriptan, timolol, oxymetazoline hydrochloride, and a CGRP antagonist.

60. The method of claim 35, wherein the composition comprises sumatriptan, timolol, oxymetazoline, and zavegepant.

61. The method of claim 35, wherein the composition comprises sumatriptan, timolol, oxymetazoline hydrochloride, and zavegepant.

62. The method of claim 35, wherein the composition comprises a triptan, timolol, oxymetazoline, and zavegepant.

63. The method of claim 35, wherein the composition comprises a triptan, timolol, oxymetazoline hydrochloride, and zavegepant.

64. The method of claim 35, wherein the composition comprises a triptan, a beta blocker, oxymetazoline, and zavegepant.

65. The method of claim 35, wherein the composition comprises a triptan, a beta blocker, oxymetazoline hydrochloride, and zavegepant.

66. The method of any one of claims 4-35, wherein the composition comprises a triptan, timolol, an alpha agonist, and zavegepant.29FH13060928.6Attorney Docket No.: STW-0012567. The method of any one of claims 28-66, wherein the composition comprises between about 0.1 to between about 2.4 weight percent sumatriptan.

68. The method of any one of claims 28-67, wherein the composition comprises about 1.2 weight percent sumatriptan.

69. The method of any one of claims 30-68, wherein the composition comprises between about 0.25 to between about 1 weight percent timolol.

70. The method of any one of claims 30-69, wherein the composition comprises about 0.5 weight percent timolol.

71. The method of any one of claims 32-70, wherein the composition comprises between about 0.05 to between about 0.2 weight percent oxymetazoline.

72. The method of any one of claims 32-71, wherein the composition comprises about 0.1 weight percent oxymetazoline.

73. The method of any one of claims 32-70, wherein the composition comprises between about 0.05 to between about 0.2 weight percent oxymetazoline hydrochloride.

74. The method of any one of claims 32-70, wherein the composition comprises about 0.1 weight percent oxymetazoline hydrochloride.

75. The method of any one of claims 35-74, wherein the composition comprises between about 0.05 to between about 0.1 weight percent zavegepant.

76. The method of any one of claims 35-75, wherein the composition comprises about 0.1 weight percent Zavegepant.

77. The method of any one of claims 4-76, wherein the composition further comprises ivermectin, etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, oxytocin, levodopa / carbidopa, caffeine, topiramate, amitryptiline, valproic acid, ergotamines, gabapentin, lotilaner, ebselen, or blue dye, or any combination thereof.

78. The method of any one of claims 4-77, wherein the composition does not include a preservative.30FH13060928.6Attorney Docket No.: STW-0012579. The method of any one of claims 4-78, wherein the pH of the composition is from about 5 to about 7.

80. The method of any one of claims 4-79, wherein the pH of the composition is about 7.

81. The method of any one of claims 4-80, wherein the composition comprises a lubricant, such as artificial tears, white petrolatum, or mineral oil.

82. The method of any one of claims 4-81, further comprising administering the composition to both eyes.

83. The method of any one of claims 4-82, wherein the subject has nausea.

84. The method of any one of claims 4-83, wherein the subject has dry eye.

85. The method of any one of claims 4-84, wherein the method reduces pupil size.

86. The method of any one of claims 4-85, wherein the method reduces red eye.

87. The method of any one of claims 4-86, wherein the method reduces ptosis.

88. The method of any one of claims 4-87, wherein the method reduces headache symptoms.

89. The method of any one of claims 4-88, wherein the method does not cause chest tightness and / or throat constriction.

90. The method of any one of claims 4-9, wherein the method reduces photophobia.

91. The method of any one of claims 4-90, wherein the composition is preservative-free.

92. A pharmaceutical composition formulated for ophthalmic administration, comprising two or more therapeutic agents selected from a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist, or pharmaceutically acceptable salts thereof.

93. The composition of claim 92, wherein the composition comprises a triptan and a beta blocker.

94. The composition of claim 92, wherein the composition comprises a triptan and a CGRP antagonist.31FH13060928.6Attorney Docket No.: STW-0012595. The composition of claim 92, wherein the composition comprises a beta blocker and a CGRP antagonist.

96. The composition of claim 92, wherein the composition comprises a beta blocker and an alpha agonist.

97. The composition of claim 92 or 93, wherein the composition comprises a triptan, a beta blocker, and an alpha agonist.

98. The composition of any one of claims 92-97, wherein the composition comprises a triptan, a beta blocker, an alpha agonist, and a CGRP antagonist.

99. The composition of any one of claims 92-98, wherein the triptan is selected from sumatriptan, ahnotriptan, eletriptan, frovatriptan, naratriptan, zolmitriptan, and rizatriptan.

100. The composition of any one of claims 92-99, where the triptan is sumatriptan.

101. The composition of any one of claims 92-100, wherein the beta blocker is selected from timolol, esmolol, and propranolol.

102. The composition of any one of claims 92-101, wherein the beta blocker is timolol.

103. The composition of any one of claims 92-102, wherein the alpha agonist is selected from apraclonidine, oxymetazoline, oxymetazoline hydrochloride, and brimonidine.

104. The composition of any one of claims 92-103, wherein the alpha agonist is oxymetazoline.

105. The composition of any one of claims 92-103, wherein the alpha agonist is oxymetazoline hydrochloride.

106. The composition of any one of claims 92-105, wherein the CGRP antagonist is selected from ubrogepant, Rimegepant, Zavegepant.

107. The composition of any one of claims 92-106, wherein the CGRP antagonist is zavegepant.

108. The composition of claim 101, wherein the composition comprises a triptan and timolol.32FH13060928.6Attorney Docket No.: STW-00125109. The composition of claim 99, wherein the composition comprises sumatriptan and a beta blocker.

110. The composition of any one of claims 101-109, wherein the composition comprises sumatriptan and timolol.

111. The composition of claim 99, wherein the composition comprises sumatriptan and a CGRP antagonist.

112. The composition of claim 106, wherein the composition comprises a triptan and zavegepant.

113. The composition of claim 106, wherein the composition comprises sumatriptan and zavegepant.

114. The composition of claim 106, wherein the composition comprises a beta blocker and zavegepant.

115. The composition of claim 101, wherein the composition comprises timolol and a CGRP antagonist.

116. The composition of claim 106, wherein the composition comprises timolol and zavegepant.

117. The composition of claim 103, wherein the composition comprises a beta blocker and oxymetazoline.

118. The composition of claim 103, wherein the composition comprises a beta blocker and oxymetazoline hydrochloride.

119. The composition of claim 101, wherein the composition comprises timolol and an alpha agonist.

120. The composition of claim 103, wherein the composition comprises timolol and oxymetazoline.

121. The composition of claim 103, wherein the composition comprises timolol and oxymetazoline hydrochloride.33FH13060928.6Attorney Docket No.: STW-00125122. The composition of claim 101, wherein the composition comprises sumatriptan, timolol, and an alpha agonist.

123. The composition of claim 103, wherein the composition comprises sumatriptan, timolol, and oxymetazoline.

124. The composition of claim 103, wherein the composition comprises sumatriptan, timolol, and oxymetazoline hydrochloride.

125. The composition of claim 103, wherein the composition comprises a triptan, timolol, and oxymetazoline.

126. The composition of claim 103, wherein the composition comprises a triptan, timolol, and oxymetazoline hydrochloride.

127. The composition of claim 103, wherein the composition comprises sumatriptan, a beta blocker, and oxymetazoline.

128. The composition of claim 103, wherein the composition comprises sumatriptan, a beta blocker, and oxymetazoline hydrochloride.

129. The composition of claim 103, wherein the composition comprises sumatriptan, timolol, oxymetazoline, and a CGRP antagonist.

130. The composition of claim 103, wherein the composition comprises sumatriptan, timolol, oxymetazoline hydrochloride, and a CGRP antagonist.

131. The composition of claim 106, wherein the composition comprises sumatriptan, timolol, oxymetazoline, and zavegepant.

132. The composition of claim 106, wherein the composition comprises sumatriptan, timolol, oxymetazoline hydrochloride, and zavegepant.

133. The composition of claim 106, wherein the composition comprises a triptan, timolol, oxymetazoline, and zavegepant.

134. The composition of claim 106, wherein the composition comprises a triptan, timolol, oxymetazoline hydrochloride, and zavegepant.34FH13060928.6Attorney Docket No.: STW-00125135. The composition of claim 106, wherein the composition comprises a triptan, a beta blocker, oxymetazoline, and zavegepant.

136. The composition of claim 106, wherein the composition comprises a triptan, a beta blocker, oxymetazoline hydrochloride, and zavegepant.

137. The composition of claim 106, wherein the composition comprises a triptan, timolol, an alpha agonist, and zavegepant.

138. The composition of any one of claims 99-137, wherein the composition comprises between about 0.1 to about 2.4 weight percent sumatriptan.

139. The composition of any one of claims 99-138, wherein the composition comprises about 1.2 weight percent sumatriptan.

140. The composition of any one of claims 101-139, wherein the composition comprises between about 0.25 to about 1 weight percent timolol.

141. The composition of any one of claims 101-140, wherein the composition comprises about 0.5 weight percent timolol.

142. The composition of any one of claims 101-141, wherein the composition comprises between about 0.05 to about 0.2 weight percent oxymetazoline.

143. The composition of any one of claims 101-142, wherein the composition comprises about 0.1 weight percent oxymetazoline.

144. The composition of any one of claims 101-141, wherein the composition comprises between about 0.05 to about 0.2 weight percent oxymetazoline hydrochloride.

145. The composition of any one of claims 101-142, wherein the composition comprises about 0.1 weight percent oxymetazoline hydrochloride.

146. The composition of any one of claims 106-145, wherein the composition comprises between about 0.05 to between about 0.1 weight percent zavegepant.

147. The composition of any one of claims 106-146, wherein the composition comprises about 0.1 weight percent zavegepant.35FH13060928.6Attorney Docket No.: STW-00125148. The composition of any one of claims 92-147, wherein the composition further comprises ivermectin, etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, oxytocin, levodopa / carbidopa, caffeine, topiramate, amitryptiline, valproic acid, ergotamines, gabapentin, lotilaner, ebselen, blue dye, or any combination thereof.

149. The composition of any one of claims 92-148, wherein the composition does not include a preservative.

150. The composition of any one of claims 92-149, wherein the pH of the composition is between around 5 to around 7.

151. The composition of any one of claims 92-150, wherein the pH of the composition is around 7.

152. The composition of any one of claims 92-151, wherein the composition comprises a lubricant, such as artificial tears, white petrolatum, or mineral oil.

153. The composition of any one of claims 92-152, wherein the composition is preservative-free.36FH13060928.6

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